This application claims benefit of U.S. Provisional Application Ser. No. 60/088,737, filed via U.S. Express Mail on Jun. 10, 1998; U.S. Provisional Application Ser. No. 60/091,666, filed via U.S. Express Mail on Jul. 2, 1998; U.S. Provisional Application Ser. No. 60/109,413, filed via U.S. Express Mail on Nov. 20, 1998; and U.S. Provisional Application Ser. No. 60/115,089, filed via Express Mail on Jan. 7, 1999, and U.S. Provisional Application Ser. No. 60/136,887 entitled xe2x80x9cAcetylcholine Enhancersxe2x80x9d filed Jun. 1, 1999 in the names of Derek T. Chalmers, Susumu Sato and Tadayuki Koda. The contents of the foregoing applications are incorporated herein by reference in their entireties.
The present invention generally relates to quinoline derivatives, more particularly to quinoline derivatives which are acetylcholine enhancers, and specifically to the acetylcholine enhancer N-[2-(1-Benzylpiperizin-4-yl)ethyl]-2,3-dihydro-9-methoxy-1H-pyrrolo[3,4b] quinolin-1-one hemifurnarate, referred to herein as Compound A (xe2x80x9cCm.Axe2x80x9d).
Alzheimer""s disease (xe2x80x9cADxe2x80x9d) is a disorder of unknown etiology. A pervasive and deleterious effect of AD is a decreasing deficit in cognitive function. Several approaches to the treatment of this disorder are currently being investigated. To date, however, only one therapeutic approach has evidenced sufficient clinical safety and efficacy to warrant approval for commercialization by the United States Food and Drug Administration (xe2x80x9cFDAxe2x80x9d). This therapeutic approach focuses on inhibition of acetylcholinesterase (xe2x80x9cAChExe2x80x9d). AChE is an enzyme that degrades the neurotransmitter acetylcholine (xe2x80x9cAChxe2x80x9d). By inhibiting this degradation process, the ACh neurotransmitter remains in the neural cleft for increased time periods, thereby increasing the chemical and functional effects of the neurotransmitter, e.g., improvement in cognitive function. Two such AChE inhibitors approved by the FDA are 1,2,3,4-tetrahydro-9-acridinamine (tacrine, THA; xe2x80x9cCOGNEXxe2x80x9d) and donepezil (E2020; xe2x80x9cARICEPTxe2x80x9d). An AChE inhibitor approved for commercialization in Europe is rivastigmine (ENA713; xe2x80x9cEXELONxe2x80x9d). A significant side effect associated with all three of these compounds is nausea and/or vomiting. This side effect can limit the maximum dose that a physician may otherwise desire to provide to a patient, for obvious reasons, e.g., the side effect may cause patients to not take all of the required doses, or the side effect may cause patients to stop taking the medication entirely.
While inhibition of AChE is one approach to resolving clinical deficits associated with AD, another approach would be to increase production of ACh. It has been reported that antagonists to the serotonin receptor 5-HT3, increase the neuronal release of ACh. See for example Ramirez, M J., et al., 712:2 Brain Res. 274 (1996); Crespi, D., et al. 35:4 Pharmacol. Res. 351 (1997); and Roychoudhurg, M. and Kulkani, S. K., 19:1 Methods Find Exp. Clin. Pharmacol. 43 (1997). It has also been reported that the density of 5-HT3 receptor recognition sites are not altered in patients with AD as compared to age-matched controls. Barnes, N. M., et al., 1:3-4 Neuroreport. 253 (1990). Antagonists to the 5-HT3 receptor are also reported to inhibit emesis (i.e., vomiting). See, e.g., Parikh, P. M. et al. 33:1 Indian J. Cancer 17 (1996).
Quinoline derivatives having AChE activity have been disclosed. U.S. Pat. Nos. 5,190,951; 5,540,934; and 5,300,517.
Compounds having multiple therapeutic mechanisms are desirable. For example, a compound that can both inhibit AChE activity and increase the neuronal production of ACh would be preferred for the treatment of neurological disorders such as AD, where the beneficial link between ACh, inhibition of AChE, and AD have been clinically established. This invention is directed to this, as well as other, important ends.
The present invention provides selected quinoline derivatives which are ACh enhancers. In some preferred embodiments, acetylcholine enhancers are provided that have the structure: 
In some preferred embodiments, the acetylcholine enhancers are pharmaceutically acceptable salts of the foregoing compounds. A particularly preferred ACh enhancer is N-[2(1-Benzylpiperizin-4-yl)ethyl]2,3-dihydro-9-methoxyl-1H-pyrrolo[3,4-b]quinolin-1-one, i.e., 
In one particularly preferred embodiment, the acetylcholine enhancer is N-[2-(1-benzylpiperizin-4-yl)ethyl]-2,3-dihydro-9-methoxy-1H-pyrrolo[3,4b]quinolin-1-one heimfumatate, i.e.: 
referred to herein as Compound A (xe2x80x9cCm.A.xe2x80x9d).
Also provided in accordance with the invention are methods for both inhibiting the enzyme acetylcholine esterase, and antagonizing the serotonin 5HT3 receptor in a system that comprises both acetylcholine esterase and the serotonin 5HT3 receptor. In preferred embodiments, the methods comprise introducing to the system an acetylcholine enhancer, preferably selected from the group consisting of compounds of formula: 
and pharmaceutically acceptable salts thereof.
In some more preferred embodiments, the compound is 
or a pharmaceutically acceptable salt thereof. In even more preferred embodiments, the acetylcholine enhancer has the formula: 
The present invention also provides pharmaceutical compositions comprising acetylcholine enhancers. In preferred embodiments, the pharmaceutical compositions comprise a compound of formula: 
or pharmaceutically acceptable salts thereof.
In further preferred embodiments, the pharmaceutical composition comprises a compound of formula: 
or a pharmaceutically acceptable salt thereof, which is preferably 
The present invention also provides methods of both inhibiting the enzyme acetylcholine esterase and antagonizing the serotonin 5HT3 receptor comprising providing an individual in need of inhibiting acetylcholine esterase and antagonizing the serotonin 5HT3 receptor with a pharmaceutical composition of the invention, which preferably comprises 